One of the most intriguing areas of current research in immunology involves a newly discovered type of helper T cells known as Th17 cells. There is a large amount of preclinical and clinical data that implicate Th17 cells, as well as IL-17, in the development of a large number of autoimmune diseases, including psoriasis, rheumatoid arthritis, asthma, and multiple sclerosis.
Activated Th17 cells isolated from chronically inflamed human tissues produce high levels of TNF-α and other cytokines. A hallmark of Th17 cells is that they express high levels of the chemokine receptor known as CCR6, which is not found on Th1 and Th2 cells. High levels of the CCR6 chemokine ligand, CCL20, have been found in psoriatic skin, in rheumatoid arthritis joint biopsies, and in asthmatic lungs.
We believe that these are potential therapeutic opportunities for a CCR6 inhibitor. We have produced several unique CCR6 inhibitor leads, which are now being optimized through medicinal chemistry approaches.
We have shown in preclinical models that an orally bioavailable, small molecule inhibitor of the chemokine receptor known as CCR6 confers protection against IL17-mediated inflammation. We have generated potent orally bioavailable CCR6 inhibitors that inhibit CCL20-mediated chemotaxis of both human and mouse CCR6-positive cells. The utility of CCR6 inhibition was tested in preclinical models of psoriasis, and demonstrated that animals treated with our CCR6 inhibitor were protected against imiquimod induced skin thickening. Histological analysis of the skin confirmed the protective effect of our CCR6 inhibitor compared to an aqueous vehicle control and significantly reduced ear-thickening induced by intradermal injections of Interleukin 23 or IL-23, a cytokine that is important for the terminal differentiation and pathogenicity of Th17 cells.
The mechanism of action for CCR6 inhibitors is different from other therapeutics targeting IL-17, because inhibition of CCR6 disrupts the recruitment of infiltrating leukocytes into the epidermis upon skin damage, thereby protecting against epidermal hyperplasia, or an abnormal increase in the number of cells on the skin. Thus, pharmacological inhibition of CCR6 with an orally bioavailable small molecule inhibitor mitigates IL-17-driven inflammation in psoriasis models, and its distinct mechanism of action suggests it may offer additional efficacy when added to current standard of care.
Recent work by others in the field has also revealed potential roles for CCR6 inhibitors in the treatment of colorectal cancer (CRC). Specifically, in a mouse CRC model, mice that are genetically deficient in CCR6, as well as wild-type mice treated with a CCR6 inhibitor develop fewer intestinal polyps.
Chemokine Receptor Inhibition as a Novel Therapeutic Approach for Psoriasis. Karen Ebsworth, Linda Ertl, Helen Wang, James Campbell, Ruiping Zhao, Jeffrey McMahon, Penglie Zhang, Israel Charo, Thomas Schall. Presented at the Society for Investigational Dermatology Annual Meeting, May 2016.
Inhibition of Chemokine Receptors CCR1 and CCR6 as Promising Therapies for Rheumatoid Arthritis
Jaen, J.; Dairaghi, D.; Leleti, M.; Powers, J.; Wang, Y.; Zhang, P.; and Schall, T. Poster Presentation at Annual European Congress of Rheumatology (EULAR) October, 2013.
CCR6 Antagonist Confers Protection Against Psoriasiform-like Disease in Mice by Limiting the Infiltration of CCR6+ Leukocytes into the Epidermis
Tan JBL; Ebsworth K; Berahovich R; Leleti M; Dairaghi D; Zhang P; Powers JP; Jaen J; Walters MJ; and Schall TS; Poster presentation at International Congress of Immunology March, 2014.